Alzheimer's disease (AD) is a common dementing (disordered memory and cognition) neurodegenerative disease associated with brain accumulation of extracellular plaques composed predominantly of the Abeta (1-40), Aβ (1-42) and Aβ (1-43) peptides (also referred to as amyloid β or Aβ), all of which are proteolytic products of amyloid precursor protein (APP). In addition, neurofibrillary tangles, composed principally of abnormally phosphorylated tau protein (a neuronal microtubule-associated protein), accumulate intracellularly in dying neurons. The Aβ (1-42) is the dominant species in the amyloid plaques of AD patients.
Familial forms of AD can be caused by mutations in the APP gene, or in the presenilin 1 or 2 genes, the protein products of which are implicated in the processing of APP to Aβ. Apolipoprotein E allelic variants also influence the age at onset of both sporadic and familial forms of AD. More recently, it has been found that a particular molecular species of Aβ, in which the peptide is oligomerized, mediates the major component of neurotoxicity observed in AD and mouse models of the disease (Walsh et al. 2002). Aβ oligomer toxicity can be manifested by dysfunction of neuronal insulin receptors (Zhao et al. 2008), and by interference with normal synaptic function, particularly in the hippocampus, by ectopic activation of glutamatergic receptors (De Felice et al. 2007; Nimmrich et al. 2008). A nanomolar affinity binding interaction was reported between Aβ oligomers and the normal cellular isoform of the prion protein PrPC (Lauren et al. 2009). Further, interaction between PrPC and various toxic signaling pathways (Solforosi et al. 2004; Lefebvre-Roque et al. 2007), including glutamate receptor subunits (Khosravani et al. 2008), may lead to a unifying mechanism for the toxicity of Aβ oligomers.
It is well recognized that immune recognition of Aβ can lead to improvement in both the pathology and behavior of transgenic mice expressing human mutant amyloid precursor protein. However, there are dangers inherent in treating human beings with “non-selective” Aβ immunotherapies. For example, autoimmune meningoencephalitis occurred in approximately 10% of patients receiving an Alzheimer's vaccine containing a non-selective Aβ immunogen (Gelinas et al. 2004; Robinson et al. 2004; Broytman and Malter 2004; Mathews and Nixon 2003). Although the resulting meningoencephalitis was likely due to cellular immune activation to Aβ, it was also shown that passively infused Aβ monoclonal antibodies (mAbs), divorced from a cellular immune response, were associated with brain microhemorrhages (Goni and Sigurdsson 2005). Another risk of non-selective immunization with Aβ is immune recognition of the parent protein APP, which is exposed at the surface of brain neurons and circulating monocytes (Jung et al. 1996; Jung et al. 1990). Such recognition of a cell surface membrane molecule may trigger lysis or interference with functioning of the extracellular domain of the APP protein, which may include trophic activity (Morimoto et al. 1998; Mileusnic et al. 2005; Mileusnic et al. 2000).
Another problem with “non-specific” recognition of Aβ peptide is that Aβ peptide is only a precursor to the toxic Aβ molecular species, the Aβ oligomers. Aβ oligomers have been shown to kill cell lines and neurons in culture (Lambert et al. 2007; Lacor et al. 2007; Ronicke et al. 2008) and block a critical synaptic activity subserving memory, referred to as long term potentiation (LTP), in slice cultures and living animals (Balducci et al. 2010; Shankar et al. 2008; Selkoe 2008; Klyubin et al. 2005; Walsh et al. 2002; Wang et al. 2002). Specific Aβ oligomers have been identified which correlate to the onset of memory defects in mice, and which when purified and infused in normal young rats reproduces negative behavioral defects found in the mice (Lesne et al. 2006). Similar research has demonstrated that PrPC may serve as a receptor for Aβ oligomers, and may transduce its toxic effects in synaptic LTP disruption (Lauren et al. 2009).
Although Aβ vaccines and monoclonal antibodies have been raised in the past against Aβ peptides, none have to date been proven to produce the desired therapeutic effect without also causing serious side effects in animals and/or humans. There is a therapeutic need for the development of biologics that arrest or slow down the progression of the disease without inducing negative and potentially lethal effects on the human body. The need is particularly evident in view of the increasing longevity of the general population and, with this increase, an associated rise in the number of patents annually diagnosed with Alzheimer's disease. It would be desirable to identify immunological epitopes that are disease-specific epitopes (DSE) and develop immunotherapies that specifically target the toxic Aβ oligomeric molecular species. It is also desirable to develop immunotherapies to target toxic Aβ oligomeric molecular species and avoid autoimmune recognition of APP at the cell surface. Such DSE epitopes would be targets for immunotherapies and prophylactic vaccines, which specifically neutralize the toxicity of target proteins. It is also desirable to develop diagnostic tools to provide an indication of populations at risk for developing AD, for differential diagnosis to distinguish AD from other dementing syndromes, and for monitoring biomarker response to AD therapy.
It is, therefore, desirable to provide a disease specific epitope that is unique to toxic Aβ oligomeric molecular species.